Non-alcoholic steatohepatitis (NASH) is directly correlated with body mass index (BMI). Cryptogenic cirrhosis (CC) is associated with NASH and obesity, and all three are independent risk factors for hepatocellular carcinoma (HCC). We hope to better understand factors inherent to steatotic livers that predispose them to liver disease, and development of HCC. The primary objective of this proposal is to examine the role of Toll-like, Receptor-4 (TLR4) signaling in the progression of fatty liver disease to HCC. Using pathology, biochemistry, and molecular biology tools we will evaluate the expression of TLR4 complex in NASH and NASH-implicated human HCC, investigate the effect of modulating TLR4 signaling on proliferative competency, and determine if TLR4 signaling is necessary for development of HCC in a murine model of NASH. We have deemed TLR4 as the nexus of a signal pathway that ultimately leads to NASH and HCC in this experimental system. Should TLR4 fail to be the nexus, it may still be implicitly involved in hepatic disease progression, and our research will clarify its role in this process.